ifinatamab deruxtecan (i-dxd) in subjects with pretreated extensive-stage small cell lung cancer (es-sclc)

Conditions: Extensive-stage Small-cell Lung Cancer

Summary: this 2-part study intends to define the recommended phase 2 dose of ifinatamab deruxtecan (i-dxd) based on the efficacy, safety, and pharmacokinetics (pk) results observed in participants with extensive-stage small cell lung cancer (es-sclc) who received at least 1 prior line of platinum-based chemotherapy and a maximum of 3 prior lines of therapy (part 1) and a minimum of two previous lines of systemic therapy (part 2). this study will also investigate i-dxd anti-tumor activity in this population.

this study will consist of 2 parts: dose optimization (part 1) and extension (part 2). in the dose optimization part of the study (part 1), approximately 80 participants with at least 1 prior line of platinum-based chemotherapy and a maximum of 3 prior lines of therapy will be enrolled. two i-dxd doses will be tested (8 mg/kg q3w and 12 mg/kg q3w). in the extension part of the study (part 2), approximately 70 participants with a minimum of two previous lines of systemic therapy will be enrolled. i-dxd will be administered at the selected dose of 12 mg/kg q3w. in part 1, eligible participants will be randomized in a 1:1 ratio to receive one of the two dose levels of i-dxd. randomization will be stratified by: 1. prior receipt or of an anti-programmed death-ligand 1 (pd-\[l\]1) antibody (yes/no) 2. the chemotherapy-free interval (ctfi) from completion of the first-line therapy to the date of documented radiological progressive disease of \<90 days vs. ≥90 days in second-line participants as well as the number of lines of therapy. thus, the stratification factor includes three categories: (1) second-line participants with ctfi \<90 days, (2) second-line participants with ctfi ≥90 days, and (3) third- and fourth-line participants.

Eligibility criteria:
inclusion criteria: participants must meet all the following criteria to be eligible for enrollment into the study: * sign and date the informed consent form (icf) prior to the start of any study-specific qualification procedures. * participant must have at least one lesion, not previously irradiated, amenable to core biopsy. * male or female subjects aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old). * histologically or cytologically documented es-sclc. * at least one measurable lesion according to recist v1.1 as assessed by the investigator. * prior therapy with at least one platinum-based line as systemic therapy for extensive-stage disease with at least two cycles of therapy (except in the case of early objective pd) and beginning with protocol version 3.0, a minimum of two previous lines of systemic therapy. * documentation of radiological disease progression on or after most recent systemic therapy. * eastern cooperative oncology group (ecog) performance status (ps) of 0 or 1. exclusion criteria: participants who meet any of the following criteria will be disqualified from entering the study: * prior treatment with orlotamab, enoblituzumab, or other b7-h3 targeted agents, including i-dxd. * prior discontinuation of an antibody drug conjugate (adc) that consists of an exatecan derivative (eg, trastuzumab deruxtecan) due to treatment-related toxicities. * clinically active brain metastases, spinal cord compression or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. * any of the following conditions within the past 6 months: cerebrovascular accident, transient ischemic attack, or another arterial thromboembolic event. * clinically significant corneal disease. * uncontrolled or significant cardiovascular disease. * history of (non-infectious) interstitial lung disease (ild)/pneumonitis that required corticosteroids, current ild/pneumonitis, or suspected ild/pneumonitis that cannot be ruled out by imaging at screening. * clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, * chronic steroid treatment (dose of 10 mg daily or more prednisone equivalent), except for low-dose inhaled steroids (for asthma/copd) or topical steroids (for mild skin conditions) or intra-articular steroid injections. * history of malignancy other than sclc within the 3 years prior to enrollment, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial gastrointestinal (gi) tract tumors and non-muscle invasive bladder cancer curatively resected by endoscopic surgery. * history of allogeneic bone marrow, stem cell, or solid organ transplant. * unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to national cancer institute- common terminology criteria for adverse events version 5.0 (nci-ctcae v5.0), grade ≤1 or baseline. * history of hypersensitivity to the drug substances, inactive ingredients in the drug product or severe hypersensitivity reactions to other monoclonal antibodies. * evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection. * has active or uncontrolled hepatitis b or c infection. * active, known, or suspected autoimmune disease. * any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, psychiatric illness/social situations, substance abuse). * has received a live vaccine within 30 days prior to the first dose of study drug. * female who is pregnant or breast-feeding or intends to become pregnant during the study. * prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the participant. * known human immunodeficiency virus (hiv) infection that is not well controlled.

Keywords: relapsed/refractory extensive-stage small-cell lung cancer ds-7300a b7-h3 antibody drug conjugate ifinatamab deruxtecan i-dxd